Luteinizing hormone: Evidence for direct action in the CNS

Abstract

Hormonal dysfunction due to aging, especially during menopause, plays a substantial role in cognitive decline as well as the progression and development of neurodegenerative diseases. The hypothalamic-pituitary-gonadal (HPG) axis has long been implicated in changes in behavior and neuronal morphology. Most notably, estrogens have proven beneficial in the healthy brain through a host of different mechanisms. Recently, luteinizing hormone (LH) has emerged as a candidate for further investigation for its role in the CNS. The basis of this is that both LH and the LH receptor are expressed in the brain, and serum levels of LH correlate with cognitive deficits and Alzheimer's disease (AD) incidence. The study of LH in cognition and AD primarily focuses on evaluating the effects of downregulation of this peptide. This literature has shown that decreasing peripheral LH, through a variety of pharmacological interventions, reduces cognitive deficits in ovariectomy and AD models. However, few studies have researched the direct actions of LH on neurons and glial cells. Here we summarize the role of luteinizing hormone in modulating cognition, and we propose a mechanism that underlies a role for brain LH in this process.

Grey matter differences associated with age and sex hormone levels between premenopausal and perimenopausal women: A voxel‐based morphometry study

“…Although sex hormones are well known for their role in procreation and the development of sex organs, they also play a critical role in brain plasticity and overall development with participation in the neuroendocrine phenomena and the establishment of behavioural patterns, including mood and cognition . Studies have confirmed that sex hormone receptors are located in the brain and that the expression of such receptors has a profound impact on brain structure, function and the formation of certain brain regions . These receptors include the PRL receptor, LH receptor and FSH receptor .…”

“…The subthalamic region plays a major role in regulating reproduction and sex hormones . The FSH and LH are mainly synthesised in the pituitary gland . Therefore, a reduction of grey matter volume in the pallidum may have an impact on the subthalamic region and subsequently affect the hypothalamic‐pituitary axis and sex hormone synthesis.…”

Luteinizing hormone downregulation but not estrogen replacement improves ovariectomy-associated cognition and spine density loss independently of treatment onset timing

“…Similarly, by observing LH levels in rats throughout the estrous cycle it has been shown that hypothalamic LH decreases during proestrus, when pituitary and serum LH levels are high (Emanuele et al, 1981). Due to the presence of LH mRNA (Palm et al, 2014), the presence of functional LH protein in the brain (Blair et al, 2015; Palm et al, 2014; Emanuel et al, 1983; Hostetter et al, 1981) and the inverted relationship between pituitary/serum LH levels and brain LH levels (Palm et al, 2014; Emanuele et al, 1981), we believe that LH is made in the brain, It is also known that LH receptor is localized to regions of the brain important for spatial reasoning, such as the hippocampus (Apaja et al, 2004). Additionally, activating LH receptor increases differentiation in PC12 cells, a neuron-like cell (Meng et al, 2007), and in vivo LH receptor activation affects courtship songs in Xenopus laevis (Yang et al, 2007) and activity and neurogenesis in rodents (Lukacs et al, 1995; Mak et al, 2007).…”

“…Therefore, one potential mechanism is that serum LH levels regulate, through some yet to be discovered feedback mechanism, the production of brain-derived LH. This, in turn, drives LH receptor signaling in the brain, which regulates cognition and plasticity (reviewed Blair et al, 2015). One such mechanism could be the short-loop feedback mechanism between the pituitary and hypothalamus (Emanuele et al, 1981; Conway and McCann, 1990).…”

Physiology of Gonadotropin-Releasing Hormone (Gnrh): Beyond the Control of Reproductive Functions

“…36 Although, as stated above, GnRH has been described to exert a control on synaptic plasticity in the hippocampus, a brain region strongly affected in AD, the relation GnRH-AD has been so far mainly described in term of its regulatory action on gonadal steroid hormone production, which may predispose to AD. However, the evidence that modifications of the brain and serum LH levels may change biochemical and cellular markers consistent with the neurodegenerative modifications observed in the AD brain 37,38 call into question the hypothesis on gonadal steroid-dependent AD susceptibility. Moreover, the observation that GnRH treatment abrogated the aging phenotype observed in mice studied by Zhang et al, 34 whereas sex steroids did not, support the notion that GnRH may be involved in AD independently of its hormonal activity.…”